1. Field of the Invention
The present invention relates to a body fluid compatible and biocompatible resin. More particularly, the present invention is concerned with a body fluid compatible and biocompatible resin for use in a medical treatment involving a contact of the resin with at least one member selected from the group consisting of a body fluid and a biological tissue, which comprises at least one substituted oxyalkylene polymer having a specific structure and having a weight average molecular weight of from 1,000 to 1,000,000. The body fluid compatible and biocompatible resin of the present invention is advantageous not only in that the adhesion of biological substances (such as a biological tissue, a cell and a platelet) to the resin can be suppressed, and the activation of a platelet, a complement and the like by the resin can also be suppressed, but also in that the resin of the present invention is highly safe for living organisms and remains stable in a body fluid for a long time. Therefore, the body fluid compatible and biocompatible resin of the present invention can be advantageously used as an ingredient, a molding material or a coating material in the production of various biological and medical products. Specific examples of biological and medical products include a membrane for an artificial kidney, a plasma separation membrane, a membrane for an artificial lung, an artificial blood vessel, an anti-adhesion membrane, a wound dressing, an artificial skin, a virus removal membrane and a leukocyte removal membrane.
Further, the resin of the present invention is amphipathic and, hence, is soluble not only in water but also in organic solvents, such as an alcohol, an ether, an ester and an aromatic hydrocarbon. Therefore, the resin of the present invention can be used in a wide variety of medical application fields. For example, the resin of the present invention in the form of a film can be used for covering external wounds, such as bedsore, burn and ulcer, and can also be used for covering wounds caused by destruction of internal tissues, such as a corium, a hypoderm, a muscle, a tendon, an articulation and a bone. Further, by utilizing the hydrophilicity and moisture retention property of the resin, the resin of the present invention can be used for producing cosmetics, and can also be used for fiber treatments. Furthermore, by utilizing the ability of the resin to prevent adsorption of a protein thereto as well as the hydrophilicity of the resin, the resin of the present invention can also be used as a component of a contact lens washing solution.
As applications other than mentioned above, for example, the resin of the present invention can be used for various treatments of a polypeptide and a protein which are derived from organisms, such as a human, a mammal, a reptile, a microbe and an insect, wherein the treatments include a separation, a purification, a concentration, a filtration, a desalting/concentration and the like. Further, the resin of the present invention can also be used for treating a medicine, an active pharmaceutical ingredient of a medicine and a raw material for a medicine, which contain the above-mentioned polypeptide or protein, wherein the treatments include a separation, a purification, a concentration, a filtration, a desalting/concentration and the like. Furthermore, the resin of the present invention can also be used as an additive for raw materials for producing an equipment used for the above-mentioned treatments or as a coating material for such an equipment.
When a compound having a pharmaceutical activity is bonded to the resin of the present invention through an amino acid or a peptide (i.e., the so-called “linker”) to form a drug complex, such a drug complex enables the delivery of the compound having a pharmaceutical activity to a target tissue without being recognized by a biological tissue when the drug complex is administered to a living body.
2. Prior Art
In recent years, studies have been made on polymeric materials having body fluid compatibility and/or biocompatibility (hereinafter, referred to as “body fluid compatible/biocompatible materials”), and the development of the application of body fluid compatible/biocompatible materials in the fields of various biological and medical products (such as a membrane for an artificial kidney, a plasma separation membrane, a catheter, a membrane for an artificial lung, an artificial blood vessel, an anti-adhesion membrane, a wound dressing and an artificial skin) is expected. In the fields of the above-exemplified biological and medical products, the body fluid compatible/biocompatible material (e.g., a synthetic polymeric material), which is foreign to a living body, is contacted with a biological tissue and/or a body fluid during the use thereof. Therefore, the body fluid compatible/biocompatible material is required to possess a satisfactory body fluid compatibility and/or biocompatibility such that interaction and/or interference is not caused between the body fluid compatible/biocompatible material and a biological tissue and/or a body fluid.
The level of body fluid compatibility and/or biocompatibility which is required of a body fluid compatible/biocompatible material depends on the use of the material and the method for using the material. Further, when a body fluid compatible/biocompatible material is used, for example, as a material which is contacted with blood, such a body fluid compatible/biocompatible material is required to have the abilities to suppress the adsorption of a protein thereto, the blood coagulation, the adhesion of a platelet thereto, the activation of a platelet and a complement, and the like.
For example, Unexamined Japanese Patent Application Laid-Open Specification No. Hei 4-152952 describes an acrylate-type biocompatible material. However, conventional acrylate-type biocompatible materials pose problems in that the monomer used as a raw material is toxic, so that the acrylate-type biocompatible material exhibits toxicity when the monomer is not completely removed from the material, and in that the acrylate-type biocompatible material which is a polymeric material cannot be decomposed at all in a living body, so that the material remains and is accumulated in a living body.
Further, a polyalkoxyalkyl (meth)acrylate, which is one of the above-mentioned acrylate-type biocompatible materials, is known to have the abilities to suppress the adhesion of a platelet thereto, and the activation of a platelet and a complement, thereby exhibiting excellent blood compatibility. However, when the polyalkoxyalkyl (meth)acrylate is accumulated in an or gan, such as a liver or a spleen, there is a danger that the organ is damaged by the accumulated polyalkoxyalkyl (meth)acrylate. Specifically, there is a danger that the polyalkoxyalkyl (meth)acrylate is separated from a substrate (e.g., by delamination of a polyalkoxyalkyl (meth)acrylate film from a substrate), so that the separated polyalkoxyalkyl (meth)acrylate is released into a body fluid and accumulated in an organ, such as a liver or a spleen. Conventionally, with respect to the polyalkoxyalkyl (meth)acrylate, only the abilities thereof to suppress the adhesion and activation of a platelet and the activation of a complement have been considered important, and the above-mentioned danger of damage to an organ has not been considered seriously. In an attempt to solve this problem, Unexamined Japanese Patent Application Laid-Open Specification No. 2001-000533 proposes a polyalkoxyalkyl (meth)acrylate product containing a specific amount of a polyalkoxyalkyl (meth)acrylate molecule having a specific high molecular weight. However, even such a polyalkoxyalkyl (meth)acrylate product is not free from the above-mentioned danger of damage to an organ and, hence, is not suitable as a biocompatible material.
WO02/22739 proposes to use an alkylene oxide copolymer in a medical equipment by utilizing the lubricity of an alkylene oxide copolymer, wherein the lubricity is exhibited due to the hydrophilicity and swelling property of the copolymer. More specifically, in this patent document, a medical equipment, a catheter and an implant are mentioned side-by-side with shaving devices and the like as examples of the use of an alkylene oxide copolymer. However, in the working example of this patent document in which the above-mentioned copolymer is synthesized, only the lubricity of the copolymer is evaluated, and there is no teaching or suggestion about the body fluid compatibility and biocompatibility of the copolymer.
Further, as an example of biodegradable and biocompatible polyacetal polymers, Japanese Patent Application prior-to-examination Publication (Tokuhyo) No. Hei 11-503481 describes the production of a polyacetal polymer obtained from an oxidized polysaccharide. This patent document describes that the polyacetal polymer has biodegradability and biocompatibility. However, in this patent document, the polyacetal polymer is only evaluated with respect to the degradability thereof using hydrochloric acid, and there is no teaching or suggestion about the biodegradability, body fluid compatibility and biocompatibility of the polymer.
On the other hand, an unsubstituted ethylene glycol homopolymer is a highly safe compound which has conventionally been used in the medical application fields. However, an unsubstituted ethylene glycol homopolymer is disadvantageous in that a drug can be introduced into this polymer only at the terminals thereof. That is, an unsubstituted ethylene glycol homopolymer is disadvantageous in that the maximum number of a drug compound which can be introduced per molecular chain of the polymer is as small as 2 (two). Therefore, when a drug complex is produced using the unsubstituted ethylene glycol homopolymer, the effective dose of the drug complex contains too large an amount of the unsubstituted ethylene glycol homopolymer such that the administration of the drug complex is practically impossible due to a heavy load on the patient. Further, an unsubstituted ethylene glycol homopolymer is generally water-soluble, so that, when used as a coating material for a shaped article, the unsubstituted ethylene glycol homopolymer is likely to dissolve out from the shaped article. Furthermore, when a mixture of an unsubstituted ethylene glycol homopolymer with a resin other than an unsubstituted ethylene glycol homopolymer is used to produce a shaped article, problems are likely to be caused due to the lack of a lipophilic subsituent in the unsubstituted ethylene glycol homopolymer, i.e., problems in that the compatibility of the unsubstituted ethylene glycol homopolymer and the other resin is poor, and in that, even when the unsubstituted ethylene glycol homopolymer and the other resin are compatibilized, the unsubstituted ethylene glycol homopolymer is likely to dissolve out from the shaped article.
With respect to a body fluid compatible/biocompatible material, not only is it demanded that the material has body fluid compatibility and biocompatibility which are appropriate for the intended use of the material and the method for using the material, but also the material is desired to be highly safe for living organisms. The reason for this is as follows. For example, when a body fluid compatible/biocompatible material is coated on a substrate and the resultant is in contact with a body fluid over a long period of time, a portion of the body fluid compatible/biocompatible material may be delaminated from the substrate and released into the body fluid. Therefore, even when the material has excellent body fluid compatibility, there is still a danger that the material is accumulated in an organ to damage the organ. Therefore, it has been desired to develop a body fluid compatible/biocompatible material which not only has the abilities to suppress blood coagulation, platelet adhesion, platelet activation and complement activation, but also exhibits high biological safety.